Precursor cells, such as neural precursor cells, have recently been shown to generate and grow, well into adulthood, in the mammalian brain and elsewhere. This finding has altered our understanding of neuroplasticity and skin plasticity and our outlook on repairing injured tissue, such as injured brain and skin, following injury or disease.
Adult neural precursor cells (NPCs) reside in two neurogenic regions in the forebrain: the subependyma lining the lateral ventricles (SEZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. Under baseline conditions, SEZ NPCs give rise to neuroblasts that migrate along a well defined pathway known as the rostral migratory stream toward the olfactory bulb, where they differentiate into interneurons. The inherent properties of proliferation, migration and neurogenesis make SEZ NPCs good candidates for contributing to neurorepair following neural insult, such as stroke, with SEZ derived NPCs having already been shown in the literature to contribute to neurogenesis following injury.
Neural insult appears to cause upregulation of multiple chemical and physical cues that enhance NPC proliferation and induce the redirection of their migration toward the lesion site, as comprehensively reviewed by Kahle et al. (Neurorehabilitation and neural Repair, vol 27 p. 469-478, June 2013), incorporated herein by reference. However, the neuroregenerative impact of endogenous NPC activity is limited. The introduction of exogenous factors appears to somewhat enhance post-insult response by NPCs, and promote functional recovery, but long-term safety concerns have limited their clinical applicability. Targeting the recruitment of NPCs to appropriate areas remains a major challenge in neurorepair efforts, and the evolution of novel methods to direct their migration is instrumental to the development of successful neurorepair strategies.
Analogously, skin progenitor cells have been found to play a role in post-insult response to skin injury. These cells may also migrate towards an injury site, and are involved in healing and recovery.
Without being limited to any particular theory, in very basic terms, it is believed that progenitor cells naturally migrate to a site of injury, then proliferate and/or differentiate into the required cells to help with healing and tissue formation at the site of injury.
Endogenous direct current electric fields (dcEFs) appear to play an important role in physiological processes, including development, wound healing, nerve growth, and angiogenesis. In vitro, external application of dcEFs has been suggested in some cases to induce the directed migration of certain cell types toward either the anode or the cathode of the electric field in a process known as electrotaxis. For example, the present inventors have shown that dcEFs are able to induce rapid and directed cathodal electrotaxis of adult SEZ-derived NPCs, but not in differentiated populations (Babona-Pilipos et al., Journal of Visualized Experiments, (2012); Babona-Pilipos et al., PLOS ONE (2011); both incorporated herein by reference) making the application of direct current electric fields a possible approach to neuroregenerative strategies.
Direct current stimulation has many challenges, especially in clinical applications. Prolonged exposure to dcEFs results in charge accumulation at the electrode-tissue interface. Such charge build-up may cause electrode corrosion followed by the formation of toxic reactive oxygen species and subsequent, often significant tissue damage due to the electrochemical reactions that occur at the electrode-tissue interface. Moreover, excessive charge accumulation at the electrodes can impede the flow of current from the stimulating electrodes. Tissue damage is generally undesirable, but especially at the site at which tissue growth is desired.
It would be desirable to be able to differentially direct migration of precursor cells with an improved side effect profile.
Biphasic current stimulation provides a generally more desirable safety profile, since it avoids charge build up and the resultant tissue damage. However, to date, biphasic current stimulation has failed to provide directed electrotaxis.